Caspase Inhibition Modulates Monocyte-Derived Macrophage Polarization in Damaged Tissues

Author:

Solier Stéphanie123ORCID,Mondini Michele4ORCID,Meziani Lydia4,Jacquel Arnaud5ORCID,Lacout Catherine12,Berghe Tom Vanden67,Julé Yvon8,Martinou Jean-Claude9,Pierron Gérard10,Rivière Julie12ORCID,Deloger Marc11ORCID,Dupuy Corinne12,Slama-Schwok Anny12ORCID,Droin Nathalie213ORCID,Vandenabeele Peter67,Auberger Patrick5,Deutsch Eric4,El-Benna Jamel14ORCID,Dang Pham My-Chan14,Solary Eric213ORCID

Affiliation:

1. INSERM U1170, Gustave Roussy, 94805 Villejuif, France

2. Faculty of Medicine, Université Paris-Sud, 94270 Le Kremlin-Bicêtre, France

3. Laboratoire d’Excellence LipSTIC, 21000 Dijon, France

4. INSERM UMR1030, Gustave Roussy, 94805 Villejuif, France

5. INSERM U1065/C3M, 06204 Nice, France

6. Inflammation Research Center (IRC), VIB, 9052 Ghent, Belgium

7. Department of Biomedical Molecular Biology, University of Ghent, 9000 Ghent, Belgium

8. Biocellvia, 13001 Marseille, France

9. Department of Cell Biology, University of Geneva, 1211 Geneva, Switzerland

10. CNRS UMR8122, Gustave Roussy, Villejuif, 94805, France

11. AMMICa, INSERM US23, CNRS UMS 3655, Gustave Roussy, 94805 Villejuif, France

12. CNRS UMR8200, Gustave Roussy, 94805 Villejuif, France

13. INSERM U1287, Gustave Roussy, 94805 Villejuif, France

14. Centre de Recherche sur l’Inflammation (CRI), Laboratoire d’Excellence Inflamex, Faculté de Médecine Xavier Bichat, Université de Paris, INSERM-U1149, CNRS-ERL8252, 75018 Paris, France

Abstract

Circulating monocytes are recruited in damaged tissues to generate macrophages that modulate disease progression. Colony-stimulating factor-1 (CSF-1) promotes the generation of monocyte-derived macrophages, which involves caspase activation. Here, we demonstrate that activated caspase-3 and caspase-7 are located to the vicinity of the mitochondria in CSF1-treated human monocytes. Active caspase-7 cleaves p47PHOX at aspartate 34, which promotes the formation of the NADPH (nicotinamide adenine dinucleotide phosphate) oxidase complex NOX2 and the production of cytosolic superoxide anions. Monocyte response to CSF-1 is altered in patients with a chronic granulomatous disease, which are constitutively defective in NOX2. Both caspase-7 down-regulation and radical oxygen species scavenging decrease the migration of CSF-1-induced macrophages. Inhibition or deletion of caspases prevents the development of lung fibrosis in mice exposed to bleomycin. Altogether, a non-conventional pathway that involves caspases and activates NOX2 is involved in CSF1-driven monocyte differentiation and could be therapeutically targeted to modulate macrophage polarization in damaged tissues.

Funder

Commissariat Général à l’Investissement

Agence Nationale de la Recherche

Ligue Nationale Contre le Cancer

Institut National du Cancer

Methusalem

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

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